• Absence of Lisch nodules in sporadic neurofibromatosis type 1 may reflect somatic mosaicism.

• Frequent genomic imbalances in chromosomes 17, 19, and 22q in peripheral nerve sheath tumours detected by comparative genomic hybridization

• The N-terminal splice product NF1-10a-2 of the NF1 gene codes for a transmembrane segment.

• Breast reconstruction in the von Recklinghausen disease patient.

• Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation.

• Kinetic profiles by topographic compartments in muscle-invasive transitional cell carcinomas of the bladder: role of TP53 and NF1 genes.

• Organisation of the pericentromeric region of chromosome 15: at least four partial gene copies are amplified in patients with a proximal

• Neurofibromatosis. Nosological considerations.

• Loss of neurofibromatosis-1 and p19(ARF) cooperate to induce a multiple tumor phenotype.

1
UI - 12056976
AU - Vabres P; Bonneau D; Larregue M
TI - Absence of Lisch nodules in sporadic neurofibromatosis type 1 may reflect somatic mosaicism.
SO - Arch Dermatol 2002 Jun;138(6):839-40; discussion 840

2
UI - 12081210
AU - Koga T; Iwasaki H; Ishiguro M; Matsuzaki A; Kikuchi M
TI - Frequent genomic imbalances in chromosomes 17, 19, and 22q in peripheral nerve sheath tumours detected by comparative genomic hybridization analysis.
SO - J Pathol 2002 May;197(1):98-107
AD - First Department of Pathology, School of Medicine, Fukuoka University, Japan.
Comparative genomic hybridization (CGH) was used to detect changes in relative chromosome copy number in 50 cases of peripheral nerve sheath tumour (PNSTs), including nine malignant peripheral nerve sheath tumours (MPNSTs), 27 neurofibromas (with three plexiform neurofibromas) and 14 schwannomas. Chromosome imbalances were frequently detected in benign as well as malignant PNSTs. In both NF1-associated and sporadic MPNSTs, the number of gains was higher than the number of losses, suggesting proto-oncogene activation during MPNST progression. NF1-asociated MPNSTs exhibited gains of chromosomes 17q and X (2/4 cases each), whereas sporadic MPNSTs showed gains of chromosome 4q (3/5 cases). On the other hand, in benign neurofibromas and schwannomas, the number of losses was higher than the number of gains, suggesting a predominant role of tumour suppressor genes in tumourigenesis. Both sporadic and NF1-associated neurofibromas exhibited losses at chromosome 22q in more than 50% of cases. These chromosomal regions may contain common chromosomal abnormalities characteristic of both types of neurofibromas. In NF1-associated neurofibromas, most frequent losses were found in chromosomes 17 [17p11.2-p13 in nine cases (60%); 17q24-25 in 6 cases (40%)] and 19 [19p13.2 in eight cases (53%); 19q13.2-qter in eight cases (53%)], whereas in sporadic neurofibromas and schwannomas losses of chromosomes 17 and 19 were detected in less than 50% of cases. Since this 17p11.2-p13 region is known to contain the tumour suppressor gene TP53, patients with NF1 may be at high risk of malignant neoplasms including MPNSTs. Gains were more frequently detected in plexiform neurofibromas (2/3 cases) than other benign tumours, suggesting proto-oncogene activation in tumourigenesis of plexiform neurofibroma. The significance of the losses of chromosome 19 in these cases is not clear at present, but in NF1-associated neurofibromas, the presence of some as yet unknown tumour suppressor genes on chromosome 19 cannot be ruled out.

3
UI - 12051738
AU - Kaufmann D; Muller R; Kenner O; Leistner W; Hein C; Vogel W; Bartelt B
TI - The N-terminal splice product NF1-10a-2 of the NF1 gene codes for a transmembrane segment.
SO - Biochem Biophys Res Commun 2002 Jun 7;294(2):496-503
AD - Department of Human Genetics, University of Ulm, Albert-Einstein-Alle 11, Ulm D 89070, Germany. dieter.kaufmann@medizin.uni-ulm.de
One important function of the neurofibromatosis type 1 (NF1) product neurofibromin is the negative regulation of Ras activity on the cell membrane. Here, we describe an alternative splice product of the N-terminus of the NF1 gene. In this splice product, termed NF1-10a-2, the 45 bp exon 10a-2 is inserted between exons 10a and 10b. Amino acid sequence analysis for motifs showed that the new splice product contains a transmembrane segment not found in wild-type neurofibromin. The overall expression was found to be very low in comparison to the expression of the wild-type mRNA in all human primary and tumor cells examined. Because transcripts were found in the majority of human tissues examined, we assume a housekeeping function of this splice product. Investigation of the intracellular localization of an NF1-10a-2-EGFP fusion protein in HeLa cells revealed a preferential localization in perinuclear granular structures. We therefore assume that NF1-10a-2 has a function on an intracellular membrane. (c) 2002 Elsevier Science (USA).

4
UI - 12087295
AU - Yamamoto Y; Kanazawa H; Sugihara T
TI - Breast reconstruction in the von Recklinghausen disease patient.
SO - Plast Reconstr Surg 2002 Jul;110(1):357-8

5
UI - 12077339
AU - Bajenaru ML; Zhu Y; Hedrick NM; Donahoe J; Parada LF; Gutmann DH
TI - Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation.
SO - Mol Cell Biol 2002 Jul;22(14):5100-13
AD - Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Individuals with the neurofibromatosis 1 (NF1) inherited tumor syndrome develop low-grade gliomas (astrocytomas) at an increased frequency, suggesting that the NF1 gene is a critical growth regulator for astrocytes. In an effort to determine the contribution of the NF1 gene product, neurofibromin, to astrocyte growth regulation and NF1-associated astrocytoma formation, we generated astrocyte-specific Nf1 conditional knockout mice (Nf1(GFAP)CKO) by using Cre/LoxP technology. Transgenic mice were developed in which Cre recombinase was specifically expressed in astrocytes by embryonic day 14.5. Successive intercrossing with mice bearing a conditional Nf1 allele (Nf1flox) resulted in GFAP-Cre Nf1flox/flox (Nf1(GFAP)CKO) animals. No astrocytoma formation or neurological impairment was observed in Nf1(GFAP)CKO mice after 20 months, but increased numbers of proliferating astrocytes were observed in several brain regions. To determine the consequence of Nf1 inactivation at different developmental times, the growth properties of embryonic day 12.5 and postnatal day 2 Nf1 null astrocytes were analyzed. Nf1 null astrocytes exhibited increased proliferation but lacked tumorigenic properties in vitro and did not form tumors when injected into immunocompromised mouse brains in vivo. Collectively, our results suggest that loss of neurofibromin is not sufficient for astrocytoma formation in mice and that other genetic or environmental factors might influence NF1-associated glioma tumorigenesis.

6
UI - 12109862
AU - Blanes A; Rubio J; Martinez A; Wolfe HJ; Diaz-Cano SJ
TI - Kinetic profiles by topographic compartments in muscle-invasive transitional cell carcinomas of the bladder: role of TP53 and NF1 genes.
SO - Am J Clin Pathol 2002 Jul;118(1):93-100
AD - Department of Pathology, University Hospital, Malaga, Spain.
We evaluated 71 muscle-invasive transitional cell carcinomas (TCCs) of the bladder by tumor compartments. Kinetic parameters included mitotic figure counting, Ki-67 index, proliferation rate (DNA slide cytometry), and apoptotic index (in situ end labeling [ISEL] of fragmented DNA using digoxigenin-labeled deoxyuridine triphosphate and Escherichia coli DNA polymerase [Klenow fragment]). At least 50 high-power fields per compartment were screened from the same tumor areas; results are expressed as percentage of positive neoplastic cells. Mean and SD were compared by tumor compartment. DNA was extracted from microdissected samples (superficial and deep) and used for microsatellite analysis of TP53 and NF1 by polymerase chain reaction-denaturing gradient gel electrophoresis. Significantly higher marker scores were revealed in the superficial compartment than in the deep compartment. An ISEL index of less than 1% was revealed in 63% (45/71) of superficial compartments and 86% (61/71) of deep compartments. Isolated NF1 alterations were observed mainly in superficial compartments, whereas isolated TP53 abnormalities were present in deep compartments. Lower proliferation and down-regulation of apoptosis define kinetically the deep compartment of muscle-invasive TCC of the bladder and correlate with the topographic heterogeneity, NF1-defective in superficial compartments and TP53-defective in deep compartments.

7
UI - 11897815
AU - Fantes JA; Mewborn SK; Lese CM; Hedrick J; Brown RL; Dyomin V; Chaganti
TI - RS; Christian SL; Ledbetter DH Organisation of the pericentromeric region of chromosome 15: at least four partial gene copies are amplified in patients with a proximal duplication of 15q.
SO - J Med Genet 2002 Mar;39(3):170-7
AD - Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
Clinical cytogenetic laboratories frequently identify an apparent duplication of proximal 15q that does not involve probes within the PWS/AS critical region and is not associated with any consistent phenotype. Previous mapping data placed several pseudogenes, NF1, IgH D/V, and GABRA5 in the pericentromeric region of proximal 15q. Recent studies have shown that these pseudogene sequences have increased copy numbers in subjects with apparent duplications of proximal 15q. To determine the extent of variation in a control population, we analysed NF1 and IgH D pseudogene copy number in interphase nuclei from 20 cytogenetically normal subjects by FISH. Both loci are polymorphic in controls, ranging from 1-4 signals for NF1 and 1-3 signals for IgH D. Eight subjects with apparent duplications, examined by the same method, showed significantly increased NF1 copy number (5-10 signals). IgH D copy number was also increased in 6/8 of these patients (4-9 signals). We identified a fourth pseudogene, BCL8A, which maps to the pericentromeric region and is coamplified along with the NF1 sequences. Interphase FISH ordering experiments show that IgH D lies closest to the centromere, while BCL8A is the most distal locus in this pseudogene array; the total size of the amplicon is estimated at approximately 1 Mb. The duplicated chromosome was inherited from either sex parent, indicating no parent of origin effect, and no consistent phenotype was present. FISH analysis with one or more of these probes is therefore useful in discriminating polymorphic amplification of proximal pseudogene sequences from clinically significant duplications of 15q.

8
UI - 12089989
AU - Badiu C; Stefanache F
TI - Neurofibromatosis. Nosological considerations.
SO - Rev Med Chir Soc Med Nat Iasi 2000 Apr-Jun;104(2):39-44
AD - Faculty of Medicine, Department of Neurology, University of Medicine and Pharmacy Gr. T. Popa Iasi, Romania.
The neurofibromatosis (NF) represent a set of conditions having different clinical manifestations, prognosis and inheritance. It has been presented--on clinical grounds--seven types of NF, but for only two of these National Institute of Health Consensus Development Conference (NIHCDC) advent a set of diagnostic criteria. The genes responsible for NF1 and NF2 were mapped to the long arm of chromosome 17 (17q11.2) and respectively 22 (22q11.2), and their protein product (neurofibromin and respectively merlin or schwanomin) was identified. Recent studies are proved that NF1 and NF2 genes act as a tumour suppressor gene. Up to now, only a limited number of mutations in these genes have been characterized but even in these cases the genotype/fenotype correlation has not provided enough information to allow speculation on the etiologic role NF1 or NF2 mutations might play in the variant forms of NF. Further studies are required to elucidate the genes functions and mutation spectrum. This should provide a framework for the molecular classification and diagnosis and the development of new therapy for NF.

9
UI - 12118376
AU - King D; Yang G; Thompson MA; Hiebert SW
TI - Loss of neurofibromatosis-1 and p19(ARF) cooperate to induce a multiple tumor phenotype.
SO - Oncogene 2002 Jul 25;21(32):4978-82
AD - Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Inactivation of the neurofibromatosis-1 (NF1) gene de-regulates RAS and cooperates with mutation or loss of the p53 tumor suppressor to induce tumorigenesis. p19(ARF) acts upstream of p53 in an oncogene checkpoint to induce apoptosis in response to activated RAS and other factors that stimulate proliferation. Therefore, we bred p19(ARF-/-) to NF1(+/-) mice to determine if loss of these genes collaborates in tumorigenesis. As expected from the embryonic lethality of NF1 null mice, no mice lacking both p19(ARF) and NF1 were born. Unexpectedly, the loss of one allele of NF1 did not greatly shorten the time to tumor formation in a p19(ARF) null background. The tumor types observed were characteristic of p19(ARF) null animals, not those associated with neurofibromatosis or those observed with NF1(+/-)/p53(+/-) mice. However, seven out of 12 animals developed multiple tumors, some with metastases. This multiple tumor phenotype was not previously observed with p19(ARF)-null mice and suggests a distinct form of cooperation between the loss of these tumor suppressors.

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